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Meta-Analysis
. 2011 Mar 16;2011(3):CD006009.
doi: 10.1002/14651858.CD006009.pub2.

Dopamine agonists for restless legs syndrome

Hanna Scholz  1 , Claudia Trenkwalder, Ralf Kohnen, Dieter Riemann, Levente Kriston, Magdolna Hornyak
Affiliations
Meta-Analysis

Dopamine agonists for restless legs syndrome

Hanna Scholz et al. Cochrane Database Syst Rev. .

Abstract

Background: According to clinical guidelines, dopamine agonists are the first-line treatment of restless legs syndrome (RLS).

Objectives: To evaluate efficacy and safety of dopamine agonists for RLS.

Search strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, plus reference lists of articles. We contacted pharmaceutical companies.

Selection criteria: We included double-blind randomised controlled trials (RCTs) of dopamine agonist treatment versus placebo or other treatment for a period of at least seven days in patients with RLS (≥ 18 years). Outcomes included the International RLS Severity Rating Scale (IRLS), Clinical Global Impressions (CGI-I), polysomnography and self rated sleep quality, quality of life, daytime functioning, and safety parameters.

Data collection and analysis: Two reviewers extracted data separately; assessed risk of bias; and contacted pharmaceutical companies and authors for additional information. We collected dropout rates due to adverse events and experience of adverse events.

Main results: We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was -5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) -6.7 to -4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were -22.4/h lower than in placebo (95% CI -27.8 to -16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD -5.3, 95% CI -8.4 to -2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably.

Authors' conclusions: The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

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Conflict of interest statement

Hanna Scholz has no conflicts of interest to declare.

Claudia Trenkwalder has been an advisor for Boehringer Ingelheim, Cephalon, Mundipharm, Orion Pharma, Novartis, Solvay, Axxonis and UCB. She has received lecture honoraria from Boehringer Ingelheim, UCB, TEVA and AstraZeneca.

Ralf Kohnen received honoraria for advisory board membership from Pfizer, USA; Axxonis, Germany; Roche, Germany; UCB, Germany; Jazzpharma, USA.

Dieter Riemann received research support from DFG, BMBF, EU (public funding) and from Takeda, Sanofi‐Aventis, Organon, Actelion and Omron. He was on the speakers bureau of Sanofi‐Aventis, Takeda, Servier, Lundbeck, Boehringer Ingelheim, GSK, Cephalon and Merz Pharmaceuticals. He was also a member of advisory boards for Sanofi‐Aventis, Lundbeck, GSK, Takeda and Actelion. Dr. Riemann declares that the above mentioned activities have no influence on the content of this article.

Levente Kriston has no conflicts of interest to declare.

Magdolna Hornyak received honoraria and/or lecture fees from Boehringer Ingelheim, Germany; GlaxoSmithKline, Germany; Roche, Germany; Pfizer Inc., Germany.

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.2 Medication subgroups: change on IRLS.
4
4
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.4 Medication subgroups: change in periodic limb movements in sleep.
5
5
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.6 Medication subgroups: change in sleep efficiency.
6
6
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.8 Medication subgroups: number of dropouts due to adverse events.
7
7
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.10 Medication subgroups: responder rates on CGI‐I.
8
8
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.12 Medication subgroups: change in self‐rated quality of sleep.
9
9
Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.14 Medication subgroups: change in quality of life.
10
10
Funnel plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.2 Medication subgroups: change on IRLS.
1.1
1.1. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 1 Change on IRLS.
1.2
1.2. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 2 Medication subgroups: change on IRLS.
1.3
1.3. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 3 Change in periodic limb movements in sleep index.
1.4
1.4. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 4 Medication subgroups: change in periodic limb movements in sleep index.
1.5
1.5. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 5 Change in sleep efficiency.
1.6
1.6. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 6 Medication subgroups: change in sleep efficiency.
1.7
1.7. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 7 Number of dropouts due to adverse events.
1.8
1.8. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 8 Medication subgroups: number of dropouts due to adverse events.
1.9
1.9. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 9 Responder rates on CGI‐I.
1.10
1.10. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 10 Medication subgroups: responder rates on CGI‐I.
1.11
1.11. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 11 Change in self rated quality of sleep.
1.12
1.12. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 12 Medication subgroups: change in self rated quality of sleep.
1.13
1.13. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 13 Change in disease specific quality of life.
1.14
1.14. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 14 Medication subgroups: change in disease specific quality of life.
1.15
1.15. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 15 Responder rates on PGI.
1.16
1.16. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 16 Medication subgroups: responder rates on PGI.
1.17
1.17. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 17 Number of patients experiencing adverse events.
1.18
1.18. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 18 Medication subgroups: number of patients experiencing adverse events.
1.19
1.19. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 19 Change in daytime tiredness.
1.20
1.20. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 20 Medication subgroups: change in daytime tiredness.
1.21
1.21. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 21 Subgroup analysis: Effect of randomisation on change on IRLS.
1.22
1.22. Analysis
Comparison 1 Dopamine agonists versus placebo, Outcome 22 Subgroup analysis: Effect of study origin on change on IRLS.
2.1
2.1. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 1 Change on IRLS.
2.2
2.2. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 2 Change in periodic limb movements in sleep.
2.3
2.3. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 3 Number of dropouts due to adverse events.
2.4
2.4. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 4 Responder rates on CGI‐I.
2.5
2.5. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 5 Change in self rated quality of sleep.
2.6
2.6. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 6 Change in quality of life.
2.7
2.7. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 7 Number of patients experiencing adverse events.
2.8
2.8. Analysis
Comparison 2 Active trials: dopamine agonists versus levodopa, Outcome 8 Change in daytime tiredness.
3.1
3.1. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 1 Change on IRLS.
3.2
3.2. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 2 Number of dropouts due to adverse events.
3.3
3.3. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 3 Responders on CGI‐I.
3.4
3.4. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 4 Change in self‐rated quality of sleep.
3.5
3.5. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 5 Change in quality of life.
3.6
3.6. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 6 Number of patients experiencing adverse events.
3.7
3.7. Analysis
Comparison 3 Active trials: lisuride vs. ropinirole, Outcome 7 Change in daytime tiredness.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

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GSK 2006 {unpublished data only}
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GSK 2008 {unpublished data only}
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GSK 2009 {unpublished data only}
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Inoue 2010 {published and unpublished data}
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Montagna 2010 {published and unpublished data}
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Partinen 2006 {published data only (unpublished sought but not used)}
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    1. CABAS‐0067‐031. A double‐blind, randomized, active‐controlled multicenter efficacy trial for the treatment of patients with Restless Legs Syndrome (RLS). http://www.clinicaltrials.gov/ct2/show/NCT00625547 (accessed 4 March 2009).
    1. Trenkwalder C, Benes H, Grote L, Happe S, Hogl B, Mathis J, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi‐center, randomized, active controlled trial. Movement Disorders 2007;22(85):696‐703. - PubMed
Trenkwalder 2008 {published and unpublished data}
    1. SP790. A multi‐center, randomized, double‐blind, placebo‐controlled, four‐arm parallel‐group trial to investigate the efficacy and safety of three different transdermal doses of rotigotine in subjects with idiopathic restless legs syndrome. http://www.clinicaltrials.gov/ct2/show/NCT00136045 (accessed 4 March 2009).
    1. Trenkwalder C, Benes H, Poewe W, Oertel WH, Garcia‐Borreguero D, Weerd AW, et al. Efficacy of rotigotine for treatment of moderate‐to‐severe restless legs syndrome: a randomised, double‐blind, placebo‐controlled trial.[see comment]. Lancet Neurology 2008;7(7):595‐604. - PubMed
Walters 2004 {published and unpublished data}
    1. SKF‐101468/194. A 12 week, double.blind, placebo‐controlled, parallel group study to assess the efficacy and safety of ropinirole in patients suffering from restless legs syndrome (RLS).. http://www.gsk‐clinicalstudyregister.com/result_detail.jsp?protocolId=101468%2f194&... (accessed 15 January 2009).
    1. Walters AS, Ondo WG, Dreykluft T, Grunstein R, Lee D, Sethi K, et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12‐week, double‐blind, randomized, parallel‐group, placebo‐controlled study. Movement Disorders 2004;19(12):1414‐23. - PubMed
Wetter 1999 {published data only}
    1. Wetter TC, Stiasny K, Winkelmann J, Buhlinger A, Brandenburg U, Penzel T, et al. A randomized controlled study of pergolide in patients with restless legs syndrome.[see comment]. Neurology 1999;52(5):944‐50. - PubMed
Winkelman 2006 {published and unpublished data}
    1. 248.543. A randomized, double‐blind, placebo‐controlled, parallel group clinical trial comparing fixed doses of 0.25 mg, 0.50 mg and 0.75 mg pramipexole (Mirapex®) administered orally to investigate the safety and efficacy in patients with idiopathic restless legs syndrome for 12 weeks. http://trials.boehringer‐ingelheim.com/res/trial/data/pdf/248.543_U05‐3094_new.pdf (accessed 4 March 2009).
    1. Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67(6):1034‐9. - PubMed

References to studies excluded from this review

Abetz 2005 {published data only}
    1. Abetz L, Arbuckle R, Allen RP, Mavraki E, Kirsch J. The reliability, validity and responsiveness of the Restless Legs Syndrome Quality of Life questionnaire (RLSQoL) in a trial population. Health & Quality of Life Outcomes 2005;3:79. - PMC - PubMed
Abetz 2006 {published data only}
    1. Abetz L, Arbuckle R, Allen RP, Garcia‐Borreguero D, Hening W, Walters AS, et al. The reliability, validity and responsiveness of the International Restless Legs Syndrome Study Group rating scale and subscales in a clinical‐trial setting. Sleep Medicine 2006;7(4):340‐9. - PubMed
Allen 1998 {published data only}
    1. Allen RP, Earley CJ, Hening WA, Walters AS, Yaffee J, Wagner ML. Pergolide treatment of the restless legs syndrome: a double‐blind placebo‐controlled study with objective assessment of leg movements. Neurology 1998;50(4 Suppl 4):A68.
Anonymous 2006 {published data only}
    1. Anonymous. Ropinirole: new indication. Restless legs: disproportionate adverse effects. Prescrire International 2006;15(85):173‐6. - PubMed
Benes 2005 {published data only}
    1. Benes H. Transdermal lisuride in patients with idiopathic restless legs syndrome: results from a placebo controlled double blind randomized multicenter 12 week dose‐finding study. Sleep Medicine 2005;6 Suppl 2:S136.
Benes 2006 {published data only}
    1. Benes H. Transdermal lisuride: short‐term efficacy and tolerability study in patients with severe restless legs syndrome. Sleep Medicine 2006;7(1):31‐5. - PubMed
Benes 2006a {published data only}
    1. Benes H, Deissler A, Rodenbeck A, Engfer A, Kohnen R. Lisuride treatment of restless legs syndrome: first studies with monotherapy in de novo patients and in combination with levodopa in advanced disease. Journal of Neural Transmission 2006;113(1):87‐92. - PubMed
Bingham 2002 {published data only}
    1. Bingham C. Pergolide for restless legs in uraemia. National Research Register, UK [http://www.nrr.nhs.uk/] 2002.
Bliwise 2005 {published data only}
    1. Bliwise DL, Freeman A, Ingram CD, Rye DB, Chakravorty S, Watts RL. Randomized, double‐blind, placebo‐controlled, short‐term trial of ropinirole in restless legs syndrome. Sleep Medicine 2005;6(2):141‐7. - PubMed
Ebell 1999 {published data only}
    1. Ebell M. Is pergolide effective in the short‐term treatment of restless leg syndrome (RLS)?. Evidence‐Based Practice 1999;2(4):5, insert 2p.
Freeman 2001 {published data only}
    1. Freeman A, Rye DB, Bliwise D, Chakravorty S, Krulewicz S, Watts RL. Ropinirole for Restless Legs Syndrome (RLS): An open label and double blind placebo‐controlled study. Neurology 2001;56(8 Suppl 3):A5.
Gunning 1999 {published data only}
    1. Gunning K, Gay C. Treatment of restless leg syndrome with pergolide. Journal of Family Practice 1999;48(4):250. - PubMed
Kinge 2005 {published data only}
    1. Kinge E, Lossius M I, Mowincel P. [Ropinirole treatment of restless legs] [Danish]. Ugeskrift for Laeger 2005;167(11):1284‐6. - PubMed
Manconi 2003 {published data only}
    1. Manconi M, Casetta I, Govoni V, Cesnik E, Ferini‐Strambi L, Granieri E. Pramipexole in Restless Legs syndrome. Evaluation by suggested immobilization test. Journal of Neurology 2003;250(12):1494‐5. - PubMed
Miranda 2003 {published data only}
    1. Miranda M, Fabres L, Kagi M, Aguilera L, Alvo M, Elgueta L, et al. [Treatment of restless legs syndrome in uremic patients undergoing dialysis with pramipexole: preliminary results]. [Spanish]. Revista Medica de Chile 2003;131(6):700‐1. - PubMed
Miranda 2004 {published data only}
    1. Miranda M, Kagi M, Fabres L, Aguilera L, Alvo M, Elgueta L, et al. Pramipexole for the treatment of uremic restless legs in patients undergoing hemodialysis. Neurology 2004;62(5):831‐2. - PubMed
Montplaisir 1998 {published data only}
    1. Montplaisir J, Nicolas A, Denesle R, Gomez‐Mancilla B. Pramipexole alleviates sensory and motor symptoms of restless legs syndrome. Neurology 1998;51(1):311‐2.
Montplaisir 2006 {published data only}
    1. 101468/188. A study of the maintained efficacy and safety of ropinirole versus placebo in the long term treatment of restless legs syndrome (RLS). http://www.gsk‐clinicalstudyregister.com/result_detail.jsp?protocolId=101468%2f188&... (accessed 15 January 2009).
    1. Montplaisir J, Karrasch J, Haan J, Volc D. Ropinirole is effective in the long‐term management of restless legs syndrome: a randomized controlled trial. Movement Disorders 2006;21(10):1627‐35. - PubMed
Morgan 2008 {published data only}
    1. Morgan JC, Ames M, Sethi KD. Response to ropinirole in restless legs syndrome is independent of baseline serum ferritin. Journal of Neurology, Neurosurgery & Psychiatry 2008;79(8):964‐5. - PubMed
Noel 1998 {published data only}
    1. Noel S, Korri H, Vanderheyden JE. Low dosage of pergolide in the treatment of restless legs syndrome. Acta Neurologica Belgica 1998;98(1):52‐3. - PubMed
Oertel 2005 {published data only}
    1. Oertel WH, Benes H, Geisler P, Eisensehr I, Garcia‐Borreguero D, Clarencach P, et al. Rotigotine patch efficacy and safety in the treatment of severe idiopathic restless legs syndrome results from a multinational double blind placebo controlled multi center dose finding study. Sleep Medicine 2005;6 Suppl 2:S159.
Partinen 2006a {published data only}
    1. Partinen M, Hirvonen K, Jama L, Alakuijala A, Hubin C, Tamminen I, et al. Effects of pramipexole on periodic limb movements (PLMs) in restless legs syndrome (RLS) a polysomnographic study. Sleep Medicine 2006;7:S126. - PubMed
Partinen 2006b {published data only}
    1. Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, et al. Clinician ratings and patient self‐ratings of improvement after 3 weeks of double‐blind placebo‐controlled pramipexole for restless legs syndrome (RLS). Sleep Medicine 2006;7:S126.
Penzel 2002 {published data only}
    1. Penzel T, Brandenburg U, Peter JH, Otto R, Hundemer HP, Lledo A, et al for the PEARLS Study Group. A new design of a polysomnography‐based multi‐center treatment study for the restless legs syndrome. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 2002;113(4):571‐8. - PubMed
Plowman 2005 {published data only}
    1. Plowman BK, Boggie DT, Morreale AP, Schaefer MG, DeLattre ML, Chan H. Clinical consultation. Sleep attacks in patients receiving dopamine‐receptor agonists. American Journal of Health‐System Pharmacy 2005;62(5):537‐40. - PubMed
Powell 2007 {published data only}
    1. Powell D. Advance reports. Patch for Parkinson's disease improves restless legs syndrome. Geriatric Medicine 2007;37(2):58.
Reading 2007 {published data only}
    1. Reading P. Parasomnias: the spectrum of things that go bump in the night. Practical Neurology 2007;7(1):6‐15. - PubMed
Reuter 1999 {published data only}
    1. Reuter I, Ellis CM, Chaudhuri KR. Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome. Acta Neurologica Scandinavica 1999;100(3):163‐7. - PubMed
Staedt 1998 {published data only}
    1. Staedt J, Hunerjager H, Ruther E, Stoppe G. Pergolide: treatment of choice in Restless Legs Syndrome (RLS) and Nocturnal Myoclonus Syndrome (NMS). Longterm follow up on pergolide. Short communication. Journal of Neural Transmission 1998;105(2‐3):265‐8. - PubMed
Stiasny 2000 {published data only}
    1. Stiasny K, Moller JC, Oertel WH. Safety of pramipexole in patients with restless legs syndrome. Neurology 2000;55(10):1589‐90. - PubMed
Stiasny 2001 {published data only}
    1. Stiasny K, Wetter TC, Winkelmann J, Brandenburg U, Penzel T, Rubin M, et al. Long‐term effects of pergolide in the treatment of restless legs syndrome. Neurology 2001;56(10):1399‐402. - PubMed
Stiasny 2002 {published data only}
    1. Stiasny K, Uberall M, Oertel WH. Cabergoline in restless legs syndrome (RLS) ‐ a double‐blind placebo‐controlled multicenter dose‐finding trial. European Journal of Neurology 2002;9 Suppl 2:50.
Tagaya 2002 {published data only}
    1. Tagaya H, Wetter T, Winkelmann J, Rubin M, Hundemer H, Trenkwalder C, et al. Pergolide restores sleep maintenance but impairs sleep EEG. Sleep Medicine 2002;3:49‐54. - PubMed
Thorpy 2005 {published data only}
    1. Thorpy M. Ropinirole in the treatment of restless legs syndrome. Current Neurology and Neuroscience Reports 2005;5(2):137‐9. - PubMed
Trenkwalder 2001a {published data only}
    1. Trenkwalder C, Brandenburg U, Hundemer P, Lledo A, Quail D, Swieca J. A randomized long‐term placebo‐controlled multicenter trial of pergolide in the treatment of Restless Legs Syndrome with central evaluation of polysomnographic data. Neurology 2001;56(8 Suppl 3):A5‐6.
Trenkwalder 2001b {published data only}
    1. Trenkwalder C, Brandenburg U, Hundemer HP, Lledo A, Quail D, Swieca J. A long‐term controlled multicenter trial of pergolide in the treatment of restless legs syndrome with central evaluation of polysomnographic data. Journal of the Neurological Sciences 2001;187 Suppl 1:S432.
Trenkwalder 2005 {published data only}
    1. Trenkwalder C, Kohen R. Augmentation and lack of efficacy with dopaminergic treatment in [patients with RLS double blind comparison between cabergoline and l‐dopa in the treatment of patients with severe restless legs syndrome. Sleep Medicine 2005;6 Suppl 2:S162.
Trenkwalder 2006 {published data only}
    1. 245.546. A double‐blind, placebo‐controlled, randomised withdrawal study of 3 months’ duration in patients suffering from idiopathic Restless Legs Syndrome who responded to a preceding, 6‐month treatment with open‐label pramipexole including titration (0.125, 0.25, 0.5, 0.75 mg orally q.n.). http://trials.boehringer‐ingelheim.com/res/trial/data/pdf/248.546_U05‐1532_new_upload.pdf (accessed 4 March 2009).
    1. Trenkwalder C, Stiasny‐Kolster K, Kupsch A, Oertel WH, Koester J, Reess J. Controlled withdrawal of pramipexole after 6 months of open‐label treatment in patients with restless legs syndrome. Movement Disorders 2006;21(9):1404‐10. - PubMed
Wetter 1998 {published data only}
    1. Wetter TC, Stiasny K, Winkelmann J, Buhlinger A, Brandenburg U, Peter JH, et al. A polysomnographic, controlled study of pergolide in the treatment of restless legs syndrome. Neurology 1998;50(4 Suppl 4):A69.
Winkelman 2005 {published data only}
    1. Winkelman J, Sethi K, Kushida C, Becker P, Mahowald M. Pramipexole is efficacious and safe in treating RLS patients results of a 12 weeks placebo controlled fixed dose study. Sleep Medicine 2005;6 Suppl 2:S74.
Yee 2004 {published data only}
    1. Yee B, Dreykluft T, Walters A, Ondo W, Sethi K, Hyman N, et al. Ropinirole versus placebo in restless legs syndrome: efficacy, safety and quality of life results from a 12‐week double‐blind international study. Internal Medicine Journal 2004;34(3):A26.

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